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Neuronal TIMP2 regulates hippocampus-dependent plasticity and extracellular matrix complexity

Summary

Scientists discovered that a protein called TIMP2, which is naturally higher in young blood, plays a crucial role in maintaining brain memory and learning ability. Using laboratory mice, they found that TIMP2 helps keep the brain’s cellular environment flexible by controlling the buildup of structural proteins around nerve connections. Without adequate TIMP2, the brain develops more rigid connections that interfere with forming new memories and creating new brain cells, mimicking changes seen in aging and cognitive decline.

Background

TIMP2 is a protein found in young blood that has been shown to improve cognitive function in aged mice. Previous studies demonstrated TIMP2’s role in brain rejuvenation, but the cellular and molecular mechanisms in the hippocampus remain unclear. This study examines how neuronal TIMP2 regulates hippocampal function through extracellular matrix remodeling.

Objective

To determine the cellular sources, expression patterns, and functional roles of TIMP2 in the hippocampus, particularly regarding synaptic plasticity, adult neurogenesis, and memory formation. The study aims to establish whether neuronal TIMP2 specifically regulates hippocampus-dependent cognitive functions.

Results

TIMP2 is predominantly expressed by hippocampal neurons and present in the extracellular space. TIMP2 deletion impairs adult neurogenesis, reduces dendritic spine density and increases immature thin spines, and causes extracellular matrix accumulation around synapses. These molecular changes correlate with deficits in hippocampus-dependent memory tasks including spatial recognition, contextual fear conditioning, and Barnes maze performance.

Conclusion

Neuronal TIMP2 regulates extracellular matrix remodeling to promote synaptic plasticity and adult neurogenesis, which are essential for hippocampus-dependent memory formation. TIMP2 acts as a critical regulator of brain plasticity through MMP2 activation and prevention of excessive extracellular matrix accumulation, positioning it as a potential therapeutic target for age-related cognitive decline.
  • Published in:Molecular Psychiatry,
  • Study Type:Experimental Research,
  • Source: PMID: 37914840, DOI: 10.1038/s41380-023-02296-5
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